Compounds for treating inflammatory diseases

ABSTRACT

The invention relates to the use of (1α.2β,4β.5α.7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0 2,4 ] nonane salts for preparing a pharmaceutical composition for the prevention and treatment of diseases associated with inflammation.

[0001] The invention relates to the use of(1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^(2,4)]nonane salts for preparing a pharmaceutical composition for theprevention and treatment of diseases associated with inflammation.

[0002] Antimuscarinics which are also often referred to in clinicalpractice as anticholinergics are firmly established in the treatment ofdiseases of the respiratory tract. For example, the administration ofipratropium bromide by inhalation (Atrovent®) as a bronchodilator isfrequently a fixed part of the treatment for COPD, a term usedhereinafter to refer to the related syndromes of chronic bronchitis,chronic obstructive bronchitis and pulmonary emphysema. Anticholinergicsare also used to treat asthma on account of their bronchodilatoryeffect.

[0003] The compound(1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^(2,4)]nonane-bromideis known from European Patent Application EP 418 716 A1 and has thefollowing chemical structure:

[0004] where X denotes bromide. The term tiotropium should be taken asbeing a reference to the free cation (1′) within the scope of thepresent invention.

[0005] Tiotropium bromide, as well as other salts of tiotropium, areknown as highly effective anticholinergic bronchodilators and cantherefore provide therapeutic benefit in the treatment of asthma orCOPD.

[0006] Tiotropium salts 1 are preferably administered by inhalation.Suitable inhalable powders packed into appropriate capsules (inhalettes)and administered using suitable powder inhalers may be used.Alternatively, they may be administered by the use of suitable inhalableaerosols. These also include powdered inhalable aerosols which contain,for example, HFA134a, HFA227 or mixtures thereof as propellant gas. Thepreparations may also be inhaled in the form of suitable solutions ofthe tiotropium salt 1.

[0007] Surprisingly, it has now been found that the antimuscarinicallyactive tiotropium salts 1 can not only be used effectively asbronchodilators in diseases such as COPD for example, but are alsocharacterised by an anti-inflammatory activity. This is due to the factthat the release of inflammatory mediators such as 15-HETE fromepithelial cells such as histamine, leukotrienes and tryptase from mastcells, chemotactic activity (for neutrophilic granulocytes, eosinophilicgranulocytes and macrophages) such as LTB4 and Interieukin 8 fromalveolar macrophages is brought about or promoted by acetylcholine andinhibited by tiotropium. Surprisingly, it has been found that thispotential, which can theoretically be attributed to all antimuscarinicactive substances, comes into play only in conjunction with an activesubstance like tiotropium which dissociates itself from the receptorvery slowly, as chemotactic and inflammatory activity has to be switchedoff permanently and not just intermittently in order to be biologicallyand clinically effective.

[0008] The invention therefore relates to the use of tiotropium salts 1for preparing a pharmaceutical composition for preventing or treatingdiseases associated with inflammation.

[0009] Preferably, the present invention relates to the use oftiotropium salts 1 for preparing a pharmaceutical composition fortreating the inflammatory component in diseases of the upper and lowerrespiratory organs including the lungs, such as for example allergic ornon-allergic rhinitis, chronic rhinitis, bronchiectasis, cysticfibrosis, asthma, COPD, idiopathic lung fibrosis, fibrosing alveolitis,skin diseases such as atopical dermatitis and urticaria as well asinflammatory bowel diseases.

[0010] Preferably, tiotropium salts 1 are used to treat inflammation inconjunction with other pulmonary diseases such as, for example, asthmaand chronic (obstructive) bronchitis with and without emphysema,bronchiectasis, cystic fibrosis and fibrosing alveolitis.

[0011] By the tiotropium salts 1 which may be used within the scope ofthe present invention are meant the compounds which contain, in additionto tiotropium as counter-ion (anion), chloride, bromide, iodide,methanesulphonate, para-toluenesulphonate or methylsulphate. Within thescope of the present invention, the methanesulphonate, chloride, bromideand iodide are preferred of all the tiotropium salts, themethanesulphonate and bromide being of particular importance. Tiotropiumbromide is of outstanding importance according to the invention.

[0012] In another aspect the present invention relates to pharmaceuticalpreparations for treating the abovementioned diseases. Withoutrestricting the scope of the invention thereto, these may containtiotropium 1′ in amounts such that each individual dose contains 0.1-80μg, preferably 0.5-60 μg, most preferably about 1-50 μg. For example,and without restricting the scope of the invention thereto, 2.5 μg, 5μg, 10 μg, 18 μg, 20 μg, 36 μg or 40 μg of 1′ may be administered persingle dose.

[0013] If tiotropium bromide is used as the preferred tiotropium salt 1according to the invention, the amounts of active substance 1′administered per single dose as specified hereinbefore by way of examplecorrespond to the following amounts of 1 administered per single dose: 3μg, 6 μg, 12 μg, 21.7 μg, 24.1 μg, 43.3 μg and 48.1 μg 1.

[0014] Use of tiotropium salts 1 according to the invention includes theuse of the solvates and hydrates thus formed, preferably the hydrates,most preferably the monohydrates.

[0015] If for example tiotropium bromide monohydrate is used as thepreferred tiotropium salt 1 according to the invention, the amounts ofactive substance 1′ administered per single dose as specifiedhereinbefore by way of example correspond to the following amounts of 1(monohydrate) administered per single dose: 3.1 μg, 6.2 μg, 12.5 μg,22.5 μg, 25 μg, 45 μg and 50 μg.

[0016] The tiotropium salts 1 are preferably administered according tothe invention by inhalation. For this purpose, the tiotropium salts 1have to be prepared in inhalable forms. Inhalable preparations includeinhalable powders, propellant-containing metering aerosols orpropellant-free inhalable solutions. Inhalable powders according to theinvention containing the tiotropium salts 1 optionally mixed withphysiologically acceptable excipients. Within the scope of the presentinvention, the term propellant-free inhalable solutions also includesconcentrates or sterile inhalable solutions ready for use. Theformulations which may be used within the scope of the present inventionare described in more detail in the next part of the specification.

[0017] A) Inhalable Powder:

[0018] The inhalable powders which may be used according to theinvention may contain 1 either on its own or in admixture with suitablephysiologically acceptable excipients.

[0019] If the tiotropium salts 1 are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare these inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably, mono- or disaccharidesare used, while the use of lactose or glucose is preferred,particularly, but not exclusively, in the form of their hydrates. Forthe purposes of the invention, lactose is the particularly preferredexcipient, while lactose monohydrate is most particularly preferred.

[0020] Within the scope of the inhalable powders according to theinvention the excipients have a maximum average particle size of up to250 μm, preferably between 10 and 150 μm, most preferably between 15 and80 μm. It may sometimes seem appropriate to add finer excipientfractions with an average particle size of 1 to 9 μm to the excipientsmentioned above. These finer excipients are also selected from the groupof possible excipients listed hereinbefore. Finally, in order to preparethe inhalable powders according to the invention, micronised activesubstance 1, preferably with an average particle size of 0.5 to 10 μm,more preferably from 1 to 6 μm, is added to the excipient mixture.Processes for producing the inhalable powders according to the inventionby grinding and micronising and by finally mixing the ingredientstogether are known from the prior art.

[0021] Inhalable powders according to the invention which contain aphysiologically acceptable excipient in addition to 1 may beadministered, for example, by means of inhalers which deliver a singledose from a supply using a measuring chamber as described in U.S. Pat.No. 4,570,630A, or by other means as described in DE 36 25 685 A. Theinhalable powders according to the invention which contain 1 optionallyin conjunction with a physiologically acceptable excipient may beadministered for example using an inhaler known by the name Turbuhaler®or using inhalers as disclosed for example in EP 237507 A. Preferably,the inhalable powders according to the invention which containphysiologically acceptable excipient in addition to 1 are packed intocapsules (to produce so-called inhalettes) which are used in inhalers asdescribed, for example, in WO 94/28958.

[0022] A particularly preferred inhaler for administering thepharmaceutical combination according to the invention in inhalettes isshown in FIG. 1.

[0023] This inhaler (Handyhaler) for inhaling powdered pharmaceuticalcompositions from capsules is characterised by a housing 1 containingtwo windows 2, a deck 3 in which there are air inlet ports and which isprovided with a screen 5 secured via a screen housing 4, an inhalationchamber 6 connected to the deck 3 on which there is a push button 8[sic] provided with two sharpened pins 7 and movable counter to a spring8, and a mouthpiece 12 which is connected to the housing 1, the deck 3and a cover 11 via a spindle 10 to enable it to be flipped open or shut.

[0024] If the inhalable powders according to the invention are packedinto capsules (inhalers) for the preferred use described above, thequantities packed into each capsule should be 1 to 30 mg, preferably 3to 20 mg, more particularly 5 to 10 mg of inhalable powder per capsule.These capsules contain, according to the invention, either together orseparately, the doses of 1′ mentioned hereinbefore for each single dose.

[0025] B) Propellant Gas-Driven Inhalation Aerosols:

[0026] Inhalation aerosols containing propellant gas which may be usedaccording to the invention may contain substances 1 dissolved in thepropellant gas or in dispersed form. The propellant gases which may beused to prepare the inhalation aerosols are known from the prior art.Suitable propellant gases are selected from among hydrocarbons such asn-propane, n-butane or isobutane and halohydrocarbons such as preferablyfluorinated derivatives of methane, ethane, propane, butane,cyclopropane or cyclobutane. The propellant gases mentioned above may beused on their own or in mixtures thereof. Particularly preferredpropellant gases are fluorinated alkane derivatives selected from TG134a(1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof.

[0027] The propellant-driven inhalation aerosols which may be usedaccording to the invention may also contain other ingredients such asco-solvents, stabilisers, surfactants, antioxidants, lubricants and pHadjusters. All these ingredients are known in the art.

[0028] The propellant-driven inhalation aerosols which may be usedaccording to the invention may contain up to 5 wt. % of activesubstance 1. The propellant-driven inhalation aerosols which may be usedaccording to the invention contain, for example, 0.002 to 5 wt. %, 0.01to 3 wt. %, 0.015 to 2 wt. % of active substance 1.

[0029] If the active substances 1 are present in dispersed form, theparticles of active substance preferably have an average particle sizeof up to 10 μm, preferably from 0.1 to 5 μm, more preferably from 1 to 5μm.

[0030] The propellant-driven inhalation aerosols according to theinvention which may be used according to the invention may beadministered using inhalers known in the art (MDIs=metered doseinhalers). Accordingly, in another aspect, the present invention relatesto the use of 1 according to the invention to prepare pharmaceuticalcompositions in the form of propellant-driven aerosols as hereinbeforedescribed combined with one or more inhalers suitable for administeringthese aerosols.

[0031] In addition, the present invention relates to the use of 1according to the invention to prepare cartridges which when fitted witha suitable valve can be used in a suitable inhaler and which contain oneof the above-mentioned propellant gas-containing inhalation aerosolsaccording to the invention. Suitable cartridges and methods of fillingthese cartridges with the inhalable aerosols containing propellant gasaccording to the invention are known from the prior art.

[0032] C) Propellant-Free Inhalable Solutions:

[0033] It is particularly preferred to use the tiotropium salts 1according to the invention to prepare propellant-free inhalablesolutions and suspensions. The solvent used may be an aqueous oralcoholic, preferably an ethanolic solution. The solvent may be water onits own or a mixture of water and ethanol. The relative proportion ofethanol compared with water is not limited but the maximum is up to 70percent by volume, more particularly up to 60 percent by volume and mostpreferably up to 30 percent by volume. The remainder of the volume ismade up of water. The solutions or suspensions containing 1 are adjustedto a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH maybe adjusted using acids selected from inorganic or organic acids.Examples of particularly suitable inorganic acids include hydrochloricacid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoricacid. Examples of particularly suitable organic acids include ascorbicacid, citric acid, malic acid, tartaric acid, maleic acid, succinicacid, fumaric acid, acetic acid, formic acid and/or propionic acid etc.Preferred inorganic acids are hydrochloric and sulphuric acids. It isalso possible to use the acids which have already formed an acidaddition salt with one of the active substances. Of the organic acids,ascorbic acid, fumaric acid and citric acid are preferred. If desired,mixtures of the above acids may be used, particularly in the case ofacids which have other properties in addition to their acidifyingqualities, e.g. as flavourings, antioxidants or complexing agents, suchas citric acid or ascorbic acid, for example. According to theinvention, it is particularly preferred to use hydrochloric acid toadjust the pH.

[0034] According to the invention, the addition of editic acid (EDTA) orone of the known salts thereof, sodium edetate, as stabiliser orcomplexing agent is unnecessary in the present formulation. Otherembodiments may contain this compound or these compounds. In a preferredembodiment the content based on sodium edetate is less than 100 mg/100ml, preferably less than 50 mg/100 ml, more preferably less than 20mg/100 ml. Generally, inhalable solutions in which the content of sodiumedetate is from 0 to 10 mg/100 ml are preferred.

[0035] Co-solvents and/or other excipients may be added to thepropellant-free inhalable solutions which may be used according to theinvention. Preferred co-solvents are those which contain hydroxyl groupsor other polar groups, e.g. alcohols—particularly isopropyl alcohol,glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents.

[0036] The preferred excipients include antioxidants such as ascorbicacid, for example, provided that it has not already been used to adjustthe pH, vitamin A, vitamin E, tocopherols and similar vitamins andprovitamins occurring in the human body. Preservatives may be used toprotect the formulation from contamination with pathogens. Suitablepreservatives are those which are known in the art, particularly cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoatessuch as sodium benzoate in the concentration known from the prior art.The preservatives mentioned above are preferably present inconcentrations of up to 50 mg/100 ml, more preferably between 5 and 20mg/100 ml.

[0037] Preferred formulations contain, in addition to the solvent waterand the tiotropium salts 1, only benzalkonium chloride and sodiumedetate. In another preferred embodiment, no sodium edetate is present.

[0038] The propellant-free inhalable solutions which may be used withinthe scope of the invention are administered in particular using inhalersof the kind which are capable of nebulising a small amount of a liquidformulation in the therapeutic dose within a few seconds to produce anaerosol suitable for therapeutic inhalation. Within the scope of thepresent invention, preferred inhalers are those in which a quantity ofless than 100 μL, preferably less than 50 μL, more preferably between 10and 30 μL of active substance solution can be nebulised in preferablyone spray action to form an aerosol with an average particle size ofless than 20 μm, preferably less than 10 μm, in such a way that theinhalable part of the aerosol corresponds to the therapeuticallyeffective quantity.

[0039] An apparatus of this kind for propellant-free delivery of ametered quantity of a liquid pharmaceutical composition for inhalationis described for example in International Patent Application WO 91/14468and also in WO 97/12687 (cf. in particular FIGS. 6a and 6 b). Thenebulisers (devices) described therein are also known by the nameRespimat®.

[0040] This nebuliser (Respimat®) can advantageously be used to producethe inhalable aerosols according to the invention containing thetiotropium salts 1. Because of its cylindrical shape and handy size ofless than 9 to 15 cm long and 2 to 4 cm wide, this device can be carriedat all times by the patient. The nebuliser sprays a defined volume ofpharmaceutical formulation using high pressures through small nozzles soas to produce inhalable aerosols.

[0041] The preferred atomiser essentially consists of an upper housingpart, a pump housing, a nozzle, a locking mechanism, a spring housing, aspring and a storage container, characterised by

[0042] a pump housing which is secured in the upper housing part andwhich comprises at one end a nozzle body with the nozzle or nozzlearrangement,

[0043] a hollow plunger with valve body,

[0044] a power takeoff flange in which the hollow plunger is secured andwhich is located in the upper housing part,

[0045] a locking mechanism situated in the upper housing part,

[0046] a spring housing with the spring contained therein, which isrotatably mounted on the upper housing part by means of a rotarybearing,

[0047] a lower housing part which is fitted onto the spring housing inthe axial direction.

[0048] The hollow plunger with valve body corresponds to a devicedisclosed in WO 97/12687. It projects partially into the cylinder of thepump housing and is axially movable within the cylinder. Reference ismade in particular to FIGS. 1 to 4, especially FIG. 3, and the relevantparts of the description. The hollow plunger with valve body exerts apressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa(about 100 to 600 bar) on the fluid, the measured amount of activesubstance solution, at its high pressure end at the moment when thespring is actuated. Volumes of 10 to 50 microliters are preferred, whilevolumes of 10 to 20 microliters are particularly preferred and a volumeof 15 microliters per spray is most particularly preferred.

[0049] The valve body is preferably mounted at the end of the hollowplunger facing the valve body.

[0050] The nozzle in the nozzle body is preferably microstructured, i.e.produced by microtechnology. Microstructured valve bodies are disclosedfor example in WO-94/07607; reference is hereby made to the contents ofthis specification, particularly FIG. 1 therein and the associateddescription.

[0051] The valve body consists for example of two sheets of glass and/orsilicon firmly joined together, at least one of which has one or moremicrostructured channels which connect the nozzle inlet end to thenozzle outlet end. At the nozzle outlet end there is at least one roundor non-round opening 2 to 10 microns deep and 5 to 15 microns wide, thedepth preferably being 4.5 to 6.5 microns while the length is preferably7 to 9 microns.

[0052] In the case of a plurality of nozzle openings, preferably two,the directions of spraying of the nozzles in the nozzle body may extendparallel to one another or may be inclined relative to one another inthe direction of the nozzle opening. In a nozzle body with at least twonozzle openings at the outlet end the directions of spraying may be atan angle of 20 to 1600 to one another, preferably 60 to 1500, mostpreferably 80 to 1000. The nozzle openings are preferably arranged at aspacing of 10 to 200 microns, more preferably at a spacing of 10 to 100microns, most preferably 30 to 70 microns. Spacings of 50 microns aremost preferred. The directions of spraying will therefore meet in thevicinity of the nozzle openings.

[0053] The liquid pharmaceutical preparation strikes the nozzle bodywith an entry pressure of up to 600 bar, preferably 200 to 300 bar, andis atomised into an inhalable aerosol through the nozzle openings. Thepreferred particle or droplet sizes of the aerosol are up to 20 microns,preferably 3 to 10 microns.

[0054] The locking mechanism contains a spring, preferably a cylindricalhelical compression spring, as a store for the mechanical energy. Thespring acts on the power takeoff flange as an actuating member themovement of which is determined by the position of a locking member. Thetravel of the power takeoff flange is precisely limited by an upper andlower stop. The spring is preferably biased, via a power step-up gear,e.g. a helical thrust gear, by an external torque which is produced whenthe upper housing part is rotated counter to the spring housing in thelower housing part. In this case, the upper housing part and the powertakeoff flange have a single or multiple V-shaped gear.

[0055] The locking member with engaging locking surfaces is arranged ina ring around the power takeoff flange. It consists, for example, of aring of plastic or metal which is inherently radially elasticallydeformable. The ring is arranged in a plane at right angles to theatomiser axis. After the biasing of the spring, the locking surfaces ofthe locking member move into the path of the power takeoff flange andprevent the spring from relaxing. The locking member is actuated bymeans of a button. The actuating button is connected or coupled to thelocking member. In order to actuate the locking mechanism, the actuatingbutton is moved parallel to the annular plane, preferably into theatomiser; this causes the deformable ring to deform in the annual plane.Details of the construction of the locking mechanism are given in WO97/20590.

[0056] The lower housing part is pushed axially over the spring housingand covers the mounting, the drive of the spindle and the storagecontainer for the fluid.

[0057] When the atomiser is actuated the upper housing part is rotatedrelative to the lower housing part, the lower housing part taking thespring housing with it. The spring is thereby compressed and biased bymeans of the helical thrust gear and the locking mechanism engagesautomatically. The angle of rotation is preferably a whole-numberfraction of 360 degrees, e.g. 180 degrees. At the same time as thespring is biased, the power takeoff part in the upper housing part ismoved along by a given distance, the hollow plunger is withdrawn insidethe cylinder in the pump housing, as a result of which some of the fluidis sucked out of the storage container and into the high pressurechamber in front of the nozzle.

[0058] If desired, a number of exchangeable storage containers whichcontain the fluid to be atomised may be pushed into the atomiser oneafter another and used in succession. The storage container contains theaqueous aerosol preparation according to the invention.

[0059] The atomising process is initiated by pressing gently on theactuating button. As a result, the locking mechanism opens up the pathfor the power takeoff member. The biased spring pushes the plunger intothe cylinder of the pump housing. The fluid leaves the nozzle of theatomiser in atomised form.

[0060] Further details of construction are disclosed in PCT ApplicationsWO 97/12683 and WO 97/20590, to which reference is hereby made.

[0061] The components of the atomiser (nebuliser) are made of a materialwhich is suitable for its purpose. The housing of the atomiser and—ifits operation permits—other parts as well are preferably made ofplastics, e.g. by injection moulding.

[0062] For medicinal purposes, physiologically safe materials are used.FIGS. 2a/b attached to this patent application, which are identical toFIGS. 6a/b of WO 97/12687, show the nebuliser (Respimat®) which canadvantageously be used for inhaling the aqueous aerosol preparationsaccording to the invention. FIG. 2a shows a longitudinal section throughthe atomiser with the spring biased while FIG. 2b shows a longitudinalsection through the atomiser with the spring relaxed.

[0063] The upper housing part (51) contains the pump housing (52) on theend of which is mounted the holder (53) for the atomiser nozzle. In theholder is the nozzle body (54) and a filter (55). The hollow plunger(57) fixed in the power takeoff flange (56) of the locking mechanismprojects partially into the cylinder of the pump housing. At its end thehollow plunger carries the valve body (58). The hollow plunger is sealedoff by means of the seal (59). Inside the upper housing part is the stop(60) on which the power takeoff flange abuts when the spring is relaxed.On the power takeoff flange is the stop (61) on which the power takeoffflange abuts when the spring is biased. After the biasing of the springthe locking member (62) moves between the stop (61) and a support (63)in the upper housing part. The actuating button (64) is connected to thelocking member. The upper housing part ends in the mouthpiece (65) andis sealed off by means of the protective cover (66) which can be placedthereon.

[0064] The spring housing (67) with compression spring (68) is rotatablymounted on the upper housing part by means of the snap-in lugs (69) androtary bearing. The lower housing part (70) is pushed over the springhousing. Inside the spring housing is the exchangeable storage container(71) for the fluid (72) which is to be atomised. The storage containeris sealed off by the stopper (73) through which the hollow plungerprojects into the storage container and is immersed at its end in thefluid (supply of active substance solution).

[0065] The spindle (74) for the mechanical counter is mounted in thecovering of the spring housing. At the end of the spindle facing theupper housing part is the drive pinion (75). The slider (76) sits on thespindle.

[0066] The nebuliser described above is suitable for nebulising theaerosol preparations which may be used according to the invention toproduce an aerosol suitable for inhalation.

[0067] If the propellant-free inhalable solutions which may be usedaccording to the invention are nebulised using the method describedabove (Respimat®) the quantity delivered should correspond to a definedquantity with a tolerance of not more than 25%, preferably 20% of thisamount in at least 97%, preferably at least 98% of all operations of theinhaler (spray actuations). Preferably, between 5 and 30 mg offormulation, most preferably between 5 and 20 mg of formulation aredelivered as a defined mass on each actuation.

[0068] However, the propellant-free inhalable solutions which may beused according to the invention may also be nebulised by means ofinhalers other than those described above, e.g. jet stream inhalers orother stationary nebulisers.

[0069] Accordingly, in a further aspect, the invention relates to theuse according to the invention of tiotropium salts 1 for preparing apharmaceutical formulation in the form of propellant-free inhalablesolutions or suspensions as described above combined with a devicesuitable for administering these formulations, preferably in conjunctionwith the Respimat®. Preferably, the invention relates to the useaccording to the invention of compounds 1 for preparing propellant-freeinhalable solutions or suspensions characterised in that they contain 1in conjunction with the device known by the name Respimat®. In addition,the present invention relates to the use according to the invention ofthe above-mentioned devices for inhalation, preferably the Respimat®,characterised in that they contain the propellant-free inhalablesolutions or suspensions according to the invention as describedhereinbefore.

[0070] The propellant-free inhalable solutions or suspensions which maybe used within the scope of the invention may take the form ofconcentrates or sterile inhalable solutions or suspensions ready foruse, as well as the above-mentioned solutions and suspensions designedfor use in a Respimat®. Formulations ready for use may be produced fromthe concentrates, for example, by the addition of isotonic salinesolutions. Sterile formulations ready for use may be administered usingenergy-operated fixed or portable nebulisers which produce inhalableaerosols by means of ultrasound or compressed air by the Venturiprinciple or other principles.

[0071] Accordingly, in another aspect, the present invention relates tothe use according to the invention of 1 in the form of propellant-freeinhalable solutions or suspensions as described hereinbefore which takethe form of concentrates or sterile formulations ready for use, combinedwith a device suitable for administering these solutions, characterisedin that the device is an energy-operated free-standing or portablenebuliser which produces inhalable aerosols by means of ultrasound orcompressed air by the Venturi principle or other methods.

[0072] The Examples which follow serve to illustrate the presentinvention in more detail without restricting the scope of the inventionto the following embodiments by way of example.

[0073] Starting Materials

[0074] Tiotropium Bromide:

[0075] The tiotropium bromide used in the following formulation examplesmay be obtained as described in European Patent Application EP 418 716A1.

[0076] In order to prepare the inhalable powders according to theinvention, crystalline tiotropium bromide monohydrate may also be used.This crystalline tiotropium bromide monohydrate may be obtained by themethod described below.

[0077] 15.0 kg of tiotropium bromide are placed in 25.7 kg of water in asuitable reaction vessel. The mixture is heated to 80-90° C. and stirredat constant temperature until a clear solution is formed. Activatedcharcoal (0.8 kg) moistened with water is suspended in 4.4 kg of water,this mixture is added to the solution containing the tiotropium bromideand the resulting mixture is rinsed with 4.3 kg of water. The mixturethus obtained is stirred for at least 15 minutes at 80-90° C. and thenfiltered through a heated filter into an apparatus preheated to anexternal temperature of 70° C. The filter is rinsed with 8.6 kg ofwater. The contents of the apparatus are cooled at 3-5° C. for every 20minutes to a temperature of 20-25° C. The apparatus is cooled further to10-15° C. using cold water and crystallisation is completed by stirringfor at least another hour. The crystals are isolated using a suctionfilter dryer, the crystal slurry isolated is washed with 9 liters ofcold water (10-15° C.) and cold acetone (10-15° C.). The crystalsobtained are dried at 25° C. in a nitrogen current over a period of 2hours.

[0078] Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).

[0079] The crystalline tiotropium bromide monohydrate thus obtained ismicronised by known methods in order to prepare the active substance inthe form of the average particle size corresponding to thespecifications according to the invention.

EXAMPLES OF FORMULATIONS

[0080] A) Inhalable powders: 1) Ingredients μg per capsule tiotropiumbromide 10.8 lactose 4989.2 Total 5000 2) Ingredients μg per capsuletiotropium bromide 21.7 lactose 4978.3 Total 5000 3) Ingredients μg percapsule tiotropium bromide × H₂O 22.5 lactose 4977.5 Total 5000

[0081] B) Inhalable aerosols containing propellant gas: 1) Suspensionaerosol: Ingredients wt. % tiotropium bromide 0.015 soya lecithin 0.2 TG134a : TG227 = 2:3 ad 100 2) Suspension aerosol: Ingredients wt. %tiotropium bromide 0.029 absolute ethanol 0.5 isopropyl myristate 0.1 TG227 ad 100 3) Solution aerosol: Ingredients wt. % tiotropium bromide0.042 absolute ethanol 30 purified water 1.5 anhydrous citric acid 0.002TG 134a ad 100

[0082] C) Propellant-free inhalable solutions: 1) Solution for use inthe Respimat ®: Ingredients mg/100 mL tiotropium bromide 148.5benzalkonium chloride 10 sodium edetate 10 hydrochloric acid (ag) ad pH2,9 water ad 100 mL 2) Solution for use in the Respimat ®: Ingredientsmg/100 mL tiotropium bromide 148.5 benzalkonium chloride 10 hydrochloricacid (ag) ad pH 2,9 water ad 100 mL 3) Solution for use in theRespimat ®: Ingredients mg/100 mL tiotropium bromide 297.1 benzalkoniumchloride 10 sodium edetate 10 hydrochloric acid (ag) ad pH 2,9 water ad100 mL 4) Solution for use in the Respimat ®: Ingredients mg/100 mLtiotropium bromide 297.1 benzalkonium chloride 10 hydrochloric acid (ag)ad pH 2,9 water ad 100 mL 5) Solution for use in the Respimat ®:Ingredients mg/100 mL tiotropium bromide 148.5 benzalkonium chloride 8sodium edetate 50 hydrochloric acid (ag) ad pH 2.5 water ad 100 mL 6)Solution for use in the Respimat ®: Ingredients mg/100 mL tiotropiumbromide 1.5 benzalkonium chloride 8 sodium edetate 10 hydrochloric acid(ag) ad pH 2.5 water ad 100 mL 7) Solution for use in the Respimat ®:Ingredients mg/100 mL tiotropium bromide 14,9 benzalkonium chloride 10sodium edetate 50 hydrochloric acid (ag) ad pH 3.5 water ad 100 mL 8)Concentrated solution: Ingredients mg/100 mL tiotropium bromide 1486.1benzalkonium chloride 20 sodium edetate 100 hydrochloric acid (ag) ad pH3.5 water ad 100 mL

What is claimed is:
 1. A method for treating disease in a warm-bloodedanimal which disease is associated with an inflammatory process whichmethod comprises administering to the animal a therapeutically effectiveamount of a salt of tiotropium.
 2. The method as recited in claim 1wherein the disease involves upper or lower or both respiratory organs.3. The method as recited in claim 1 wherein the disease is selected fromallergic rhinitis, non-allergic rhinitis, chronic rhinitis,bronchiectasis, cystic fibrosis, asthma, COPD, idiopathic lung fibrosisand fibrosing alveolitis.
 4. The method as recited in claim 1 whereinthe disease is selected from dermatitis, urticaria and inflammatorybowel disease.
 5. The method as recited in claim 1 wherein thetiotropium salt is selected from chloride, bromide, iodide,methanesulphonate, paratoluenesulphonate and methylsulphate.
 6. Themethod as recited in claim 5 wherein the tiotropium salt ismethanesulphonate, chloride, bromide or iodide.
 7. The method as recitedin claim 6 wherein the tiotropium salt is methanesulphonate or bromide.8. The method as recited in claim 1 wherein the tiotropium salt isadministered via inhalation.